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Author
Topic: Need advice! (Read 7045 times)

I am on Reyataz (w/ Norvir boost), and Truvada. I am resistant to all the NRTI's (tenofovir works a little, according to the tests). My viral load went up from undetectable (for over a year), to 218. Small increase, but the doc wanted me to add AZT, which I haven't taken since I was first diagnosed in 1991.

Does AZT make you feel tired right away? I've been on it a week and just can't nap enough, although I may have a slight flu or a reaction from my flu shot that I had the same day I started the AZT.

Anyway, I'm starting to get FREAKED out that I'm resistant to all the NRTI's and 2 of the NNRTI's. What happens next? Can you get by without that class of drugs? Should I really add AZT, or should I add another PI instead, or is 218 nothing to worry about?

If you have multiple resistant mutations called TAMs, then adding AZT would not help. The one situation in which AZT would help is if you have a K65R mutation which makes the virus resistant to tenofovir, abacavir and videx but makes it hypersensitive to AZT. That only works though if there are no TAMs. It would help to know the actual genotype test to make this determination.

As far as using 2 boosted PIs, that might be the more logical option, but that would work best if they can be combined with a third active drug such as Fuzeon. But if you are going the Fuzeon route, it might be just as well to combine it with Prezista, the new PI, boosted with Norvir. There are other classes of drugs in the pipeline such as Merck's integrase inhibitor which is now on expanded access. So there are options left even if you cannot use any of the NRTIs or NNRTIs.

I would have another viral load test done before making a decision about adding another drug or otherwise changing your regimen. I've been mostly undetectable (<50) for the past 18 months, but there have been a couple of "blips" during that time, where my VL went over the magic number of 50. The past five VL's have all been undetectable.

Re: "My viral load went up from undetectable (for over a year), to 218" - what Allan said. It is most likely a blip. So me personally, I would stop the AZT til this is done.

On resistance: what Gerry said, some mutation info from a genotype would help decide whether AZT is worth adding or just a waste of time.

If you are resistant to all the NRTIs you probably have the HIV with the M184V mutation, which is extra sensitive to the tenofovir in Truvada. If you have been undetectable for a year on boosted Reyataz + Truvada it is most likely good enough. :-)

My view: adding in AZT will most likely do nothing, or at an outside chance not much.

Given the number of other nuke mutations here, The AZT may add small degree of additional action against the M184V HIV in your viral mix, but overall probably not enough to be worthwhile, probably not enough to significantly enhance the tenofovir's action on this and very possibly do nothing extra at all. It wont be doing anything else.

Tenofovir is between full and partial effectiveness. Cos you got undetectable using it, and stayed there for a year, it's effectiveness seems to be higher rather than lower.

A critical issue for you is consistent timing on the nukes, and especially not missing a day. Tenofovir resistant varieities can appear 1 day after missing/being very late with a dose. You do not want to create conditions for a seriously tenofovir-resisting mutation to appear. Taking your combo in good time every day will avoid this and assist in maintaining your current combo as viable.

I have geno and phenos from 2001. I do have the M184V mutation. These tests are hard to read but maybe this can help you drug detectives:

M41LE44DD67NV118IM184VL210WT215Y

Unfortunately, you have the 41L/210W/215Y TAM pattern (selected for by being on AZT and remaining detectable). This pattern is associated with extensive NRTI resistance, including significant resistance to Viread. The M184V makes you completely resistant to 3TC and FTC as well. So in your current combo, you are essentially just relying on boosted Reyataz for viral suppression. Adding AZT is pretty much useless with this genotype pattern.

The next question to ask now is whether or not the "blip" represents early treatment failure. Considering that you are essentially on boosted Reyataz monotherapy, I would think that treatment failure should be ruled out at this point. The problem is your current viral load is too low to do another resistance test.

You might want to get a second opinion with Dr. Gallant at Hopkins: LINK. You didn't mention what your current CD4 count is, which would also factor in making your next decisions (i.e., if it's high enough, can you potentially take a treatment break?). This might be a good time to consider Fuzeon with Prezista or a double-boosted PI, if your CD4 count would not allow you to take a treatment break.

I kind of agree with newt and gerry here. It sounds like a blip, it certainly is the right magnitude. However, you should check to see what the next viral load test shows.

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NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

This pattern is associated with extensive NRTI resistance, including significant resistance to Viread. The M184V makes you completely resistant to 3TC and FTC as well. So in your current combo, you are essentially just relying on boosted Reyataz for viral suppression

Gerry, I disagree, there's a very good chance the nukes are doing a bit, or more than a bit, in practice. Viread looks like it's still fully-partially effective according to the Stanford phenotype database (or slightly different version here). M184V is well known to completely wipe 3TC/FTC but this doesn't always affect viral suppression.

Anyway what's wrong with boosted Reyataz monotherapy if it works? The proof of the pudding is in the eating, the target is undetectable, and that's the general picture now for 12+ months.

This is likely to be a blip. If the next viral load test shows a fig in the low 100s, I personally would be reconsider then.

This is from the same Stanford Paper on genotype resistance (page 12).

"Complete loss of response to abacavir appears to require the combination of three or more TAMs together with the mutation M184V (Lanier et al., 1999; Katlama et al., 2000; Brun-Vezinet et al., 2003). The presence of 1-2 TAMs has little effect on the virologic response to the addition of didanosine to a stable regimen; 3 TAMs causes a reduction in response; complete loss of response appears to require four TAMs (Molina et al., 2003). In the presence of M41L, L210W, and T215Y, there is little virologic response to tenofovir (Barrios et al., 2003; McColl & Miller, 2003; Squires et al., 2003). In contrast, mutations at positions 67, 70, and 219, and the T215F substitution have less impact on tenofovir susceptibility and virologic response (Barrios et al., 2003; McColl & Miller, 2003; Squires et al., 2003)."

For people with multiple TAMs, there are two pathways that can happen: the 67/70/219/215F TAM combination is considered more “benign” because Viread still works in this situation (this was what happened with Jena and that's why she was able to use the ATV/r + TDF + 3TC successfully). On the other hand, in the presence of a 41L/210W/215Y TAM pattern, Viread works very little against the virus. I would agree that boosted Reyataz works in certain situations where more options are available down the road, but if one uses it in a situation when the PI class is the only remaining class of ARV that is reliable (other than Fuzeon), I would have gone more aggressive instead of just being on essentially a boosted Reyataz monotherapy and paired it up with something to which the virus is fully susceptible (like Fuzeon) to increase the chances of durability of suppression, and not just to achieve initial suppression.

CD4 count was 277, and it's been between 200-300 for the past 5 years or so, over varying therapies.

It does not look like you have too much room to interrupt treatment. You might want to ask your question at the Hopkins site I linked above with Dr. Gallant (he wants a little more detailed treatment history). The one sure thing is adding the AZT is not doing anything to help viral suppression. I'd still think it would be a good idea to consider Fuzeon + double boosted PI (such as Kaletra/Invirase) or Prezista at this point or somewhere in the near future, unless you want to hold off considering the Fuzeon until Merck's integrase inhibitor comes out. Also, when you said you were NNRTI resistant, which genotype(s) were involved? You might be able to use the TMC-125 as well if you only have one resistant NNRTI genotype (such as K103N).

Gerry, I agree your reading could be right, but Stanford's phenotype query, using Virologic's database, gives a fold change of between 1.1 and 2.3 for tenofovir for this mutation pattern, with a median of 1.6. Since a fold change of 1.0 = 100% effective and tenofovir's cut-off for effectiveness is 3.0, in practice this says to me tenofovir is active.

So boosted PI monotherapy or some nuke activity.... we will of course never know.

And it really doesn't matter. The target is undetectable and the right time to change is on treatment failure ie 2 consecutive tests of a viral load 250-500+. Despite the compelling information on paper I see no evidence of clinical failure here (yet).

Of course, an aggressive approach eg switch, add in T20 is an option, but me, I see a blip, until there's 2 viral load tests in a row of 250-500+ I see a blip.

Gerry, I agree your reading could be right, but Stanford's phenotype query, using Virologic's database, gives a fold change of between 1.1 and 2.3 for tenofovir for this mutation pattern, with a median of 1.6. Since a fold change of 1.0 = 100% effective and tenofovir's cut-off for effectiveness is 3.0, in practice this says to me tenofovir is active.

I think lagunaguy has phenotype results as well, so it would be good to know the tenofovir fold change from his results. He did say in his initial post that tenofovir "works little" and I assume that's from the pheno results. In this situation though, working little is probably not good enough which leaves the Reyataz quite vulnerable.

Quote

Despite the compelling information on paper I see no evidence of clinical failure here (yet).

That's the $100K question, isn't it? Is this a blip or is this early treatment failure? The good thing is even if this represents early treatment failure, Reyataz tends to select for the 50L mutation first which does not affect the other PIs at all. This is one of those situations where I would re-check the VL sooner rather than later.

Gerry and Matt- you guys are great, you are making me feel better about all this, just in time for Christmas!

Anyway, NNRTI's: I have the Y188L, and I assume that's bad because it's been a long time since I've taken any of those drugs, in fact never took Sustiva.

I do have Pheno type results, but not sure what you are looking for on that. There is a bar graph for each drug and then as far as numbers it goes like this:Ziagen 10Videx 2.9Epivir >>>Zerit 4.6Hivid 4.11Retrovir 711

Rescriptor 31Sustiva 268Viramune >>>

All the PI's have nothing- at that point I hadn't taken any PI's I don't think.

***tenofovir is not on the list- my guess is that it was not out at that time? (2001)

The Y188L causes high grade resistance to Viramune and Sustiva and intermediate resistance to Rescriptor. So in essence, the currently available NNRTIs are out. However, since you only have one NNRTI resistant genotype, the next generation NNRTI TMC-125, which is already in Phase 3 trials and on expanded access, would still be useful in your situation.

The fact that you haven't taken any other PIs prior to the current Reyataz/Norvir would also work in your favor in terms of future options.

I guess what's important to keep in mind is whatever happens from here on, you do have other viable options, even if the current NRTIs and NNRTIs aren't usable or reliable.

I still don't understand why your doc added AZT, though. I guess this is something you would need to ask him. It might also be good to ask him what his plans are if the next VL is still detectable, as well as when he is planning to repeat it. Being vigilant is the key here because you don't want a situation in which PI mutations may accumulate if the detectable VL happens to persist.

... but I stand by my guns on getting another vl test (er, right away) before you fret for real - if it shows a vl of 250-500+ again, do consider a new combo. You still have lots of options, probably beginning with Reyataz + another PI, moving on to stab-my-butt but effective T20 and then the newbies like Maraviroc (looks v gd this so far) etc. If a change is on the cards, it's important your doc gets a new genotype/phenotype test. You need a vl of 500+ for this. The results will help you choose new meds.

But until then, make merry, it's Christmas or sommat (but take your tabs on time )

I'm not sure TMC-125 is going to be the ticket either. I DO think another viral load test is in order. You can discuss the issue after that.

R

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NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

They could, but it seems that of all the drugs, people want to dump the nukes the most. How about they come up with something different that works better vs more of the same..

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NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

I'm not sure TMC-125 is going to be the ticket either. I DO think another viral load test is in order. You can discuss the issue after that.

No, certainly not by adding it by itself to a failing regimen, assuming that it is failing. But it can certainly be used as part of a new regimen by adding it to other active drugs in this situation, such as a different boosted PI or Fuzeon or the new integrase inhibitor. So there are timing issues in terms of when/if a new regimen is needed.

Thanks everyone for looking at this. I'm going to do another vl test in a month and see where it's at, and I'll be back to let you know. Hopefully it's just a blip.

I hope that science works on some new NRTIs, that would be nice.

I do believe that if you end up needing a new regimen, you would need to look beyond the NRTIs because of your resistant genotypes. Certainly not the currently available ones. And the new ones on the horizon are too early in their development phase to be of benefit to you. Keep us posted on further developments

No, my point was that for some reason TMC-125 doesn't appear as good as it should at controlling VL in people with resistance...or at least that is what I am reading. It has fantastic in vitro properties, but for some reason in vivo it doesn't do as well as it should. I don't think that is a slight on the makers, just that we might have to rethink why.

R

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NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

No, my point was that for some reason TMC-125 doesn't appear as good as it should at controlling VL in people with resistance...or at least that is what I am reading. It has fantastic in vitro properties, but for some reason in vivo it doesn't do as well as it should. I don't think that is a slight on the makers, just that we might have to rethink why.

Rich:

You may have been referring to TMC 125-227 study. I misinterpreted the data in that study when I first read about it on Aidsmap. But after further analysis and asking, it was really the study design that led to the inferior results, which I tried to clarify later in an earlier thread.

You are right. Given that patients with M184V and TAM mutations responded poorly to TMC-125, having an initial 1 log reduction in viral load, and rebound to baseline, and these are the mutations that this person has - would TMC-125 really be a good thing to suggest for this person?

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NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

You are right. Given that patients with M184V and TAM mutations responded poorly to TMC-125, having an initial 1 log reduction in viral load, and rebound to baseline, and these are the mutations that this person has - would TMC-125 really be a good thing to suggest for this person?

Yes, because he only has 1 NNRTI mutation. However, TMC-125 should not be used the way it was used in the 227 study, in which it was simply thrown in and added to a failing regimen. The correct way to use TMC-125 in this situation would be to add it to other meds that would be active as well, such as Prezista (or other active boosted PIs) or Fuzeon, or even the new integrase inhibitor.

Really? Even though some studies say, "Even patients with only one NNRTI mutation experienced rapid failure if they also had a high level of resistance to nucleoside analogues"

I might be wrong, but isn't this what the guy has?

My point really is that given the nature of the VL from the poster of the thread, the advice boils down to going on two drugs still in development and Fuzeon. With a VL in the 200s? Doesn't that appear to be a bit rash?

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NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Once again, Rich, I think you are misinterpreting the study and my answer to your question. My initial response to lagunaguy was if he needed to change regimens, he would need to consider Fuzeon and a double boosted PI or Prezista/Norvir (or Aptivus/Norvir, which I did not add) which are the ones available now. There is still utility with TMC-125 but only if it's used with optimized background regimen; i.e., added to active drugs such as the ones I already mentioned (not by just combining TMC-125 with 2 NRTIs which was what was done in study 227, which was the reason the regimen failed; the NRTI mutations did not directly cause the TMC-125 failure, rather the number of NRTI mutations correlated with the number of NNRTI mutations). Please look at the raw data and the investigators' conclusions on this link rather than the aidsmap article because the aidsmap article had some very misleading statements. If you still have doubts, then I suggest that you ask some experts from thebody.com or Hopkins (I did the latter already).

Actually, I am confused by their conclusions. Are you/they saying that TMC-125 didn't do well because the OBT didn't control viremia and didn't help the new NNRTI? But the PI did because they didn't have any PI resistance?

R

« Last Edit: December 17, 2006, 01:30:26 AM by HIVworker »

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NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

"When Tibotec's Brian Woodfall wound up his slide talk, the message seemed clear: TMC125 may indeed have a sturdier barrier to resistance than efavirenz or nevirapine, and it may rein in virus bearing (only) the fearsome K103N mutation. But it's not an anti-resistance elixir that will stifle virus already sporting a string of reverse transcriptase inhibitor mutations."

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NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Hi guys. I had posted the same initial question of my problem on The Body and here is the response from Dr. David Wohl, MD. Seems to explain the AZT thing a little more.

>Generally, I confirm a newly detectable viral load before I change anything. In many cases, an unexpected small rise in viral load is a blip and repeat testing shows that the viral load is back down to less than 50. Was it a small burst of viral replication or lab error? Who knows.But in your case, I would be inclined to add the AZT no matter what, unless your viral load increases even higher (>1000). Your virus has a bunch of resistance mutations that reduce its susceptibility to a number of HIV drugs, including the Truvada you are taking. The FTC in Truvada is no longer able to stop your virus from replicating and there are AZT resistance mutations that will make the other half of Truvada, tenofovir, less effective too.So, why add AZT if your virus is resistant to it? If your virus level turns out to be very low (under 1000) I would do it to try to put pressure on the virus to keep the AZT resistant virus as the majority strain of HIV in your system. AZT resistant virus likely does not work as well as non-resistant virus. Further, AZT resistant virus has a hard time also being fully resistant to tenofovir. Therefore, AZT may keep around weak virus and 'protect' your HIV from developing the major tenofvir resistance mutation. Likewise, keeping FTC on board, helps maintain the mutation against this drug and such virus is also less active. All this may drive the viral load down if it is at a very low level.But, if your viral load is repeated and is >1000, I would favor a complete change in your therapy to as many active HIV drugs as possible, rather than just add some AZT.<

The Body and Johns Hopkins AIDS Center both have doctors who answer questions about HIV treatment. I haven't used The Body, but Dr. Joel Gallant at the Johns Hopkins website has been an invaluable help to me over the years (http://qa.hopkins-aids.org/forum/). He can be very funny (i.e., sarcastic) with some of the more off-the-wall questions from the worried well.

In addition to what THE BODY said, I think they gave you AZT because of M184V, which makes HIV a bit more sensitive to AZT and dulls the effect of the TAM mutations.

R

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NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

I just noticed going through Hopkins' Q&A which I read quite regularly that you also asked Dr. Gallant for an opinion and here was his answer (he didn't know about the Y188L resistant NNRTI mutation but he took this into consideration in his response as well):

Dr. Gallant: "Your resistance results show very high-level resistance to all of the nucleoside analogs, and therefore you're essentially on Reyataz/Norvir alone. The Truvada is probably doing nothing, and neither is the AZT that you just added. Someone with this resistance pattern would normally be treated with a PI plus another agent from a different class. If you've never taken an NNRTI, then Sustiva or Viramune would be an option. If you're already resistant to NNRTIs, then you would combine the PI with T20 or with one of the investigational agents current available through expanded access."

You may want to discuss with your doc both Dr. Wohl's and Dr. Gallant's responses. You're already scheduled for another VL so you probably don't need to do anything else till then, but it might help to open up this discussion with your doc to figure out future plans.

"In the presence of TAMs, M184V decreases susceptibility to didanosine, zalcitibine, and abacavir and increases susceptibility to zidovudine, stavudine, and tenofovir. Resensitization, however, can be overcome by the presence of four or more zidovudine resistance mutations."